CCR2 and CCR5 chemokine receptors differentially influence the development of autoimmune diabetes in the NOD mouse

Abstract

The infiltration of monocytes represents an important early event in the development of autoimmune diabetes in NOD mice. Given that chemokines are key regulators of leukocyte trafficking, we examined the requirement for the chemokine receptors β(CC)-chemokine receptor-5 (CCR5) and β(CC)-chemokine receptor-2 (CCR2), which recruit monocytes, in disease development in the NOD mouse. Whereas the onset of diabetes was significantly delayed in CCR2-/-NOD mice (25% at 30 weeks) compared to NOD mice (50% at 28 weeks), the pathogenesis of diabetes was accelerated in CCR5-/-NOD mice (75% at 23 weeks). The rapid development of diabetes in CCR5-/-NOD mice was associated with aggressive destructive insulitis and was accompanied by altered leukocyte migration into islets. In contrast, CCR2-/- NOD mice exhibited delayed inflammatory cell recruitment. Nevertheless, total diabetogenic splenocytes from CCR2-/-NOD and CCR5-/-NOD showed similar capability to adoptively transfer diabetes into NOD.scid recipients. Importantly, our data suggest that targeting of CCR2 may lead to therapies against Type 1 diabetes.